Site-specific synthesis and reactivity of oligonucleotides containing stereochemically defined 1,N2-deoxyguanosine adducts of the lipid peroxidation product trans-4-hydroxynonenal.

Wang H, Kozekov ID, Harris TM, Rizzo CJ
J Am Chem Soc. 2003 125 (19): 5687-700

PMID: 12733907 · DOI:10.1021/ja0288800

trans-4-Hydroxynonenal (HNE) is a major peroxidation product of omega-6 polyunsaturated fatty acids. The reaction of HNE with DNA gives four diastereomeric 1,N(2)-gamma-hydroxypropano adducts of deoxyguanosine; background levels of these adducts have been detected in animal tissue. Stereospecific syntheses of these four adducts at the nucleoside level have been accomplished. In addition, a versatile strategy for their site-specific incorporation into oligonucleotides has been developed. These adducts are destabilizing as measured by melting temperature when compared to an unadducted strand. The thermal destablization of the adducted 12-mers ranged from 5 to 16 degrees C and is dependent on the absolute stereochemistry of the adduct. The HNE adducts were also examined for their ability to form interstrand DNA-DNA cross-links when incorporated into a CpG sequence. We find that only one of the HNE stereoisomers formed interstrand DNA-DNA cross-links.

MeSH Terms (11)

Aldehydes Binding Sites Circular Dichroism Deoxyguanosine DNA DNA Adducts Lipid Peroxidation Nuclear Magnetic Resonance, Biomolecular Oligonucleotides Stereoisomerism Substrate Specificity

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